Arsenic has been shown to cause non-melanoma skin cancer in highly-exposed populations, however, little information is available on this association for persons exposed to arsenic levels typical of the U.S. population. Data suggest an association of arsenic exposure with bladder cancer, however, this association requires further study, and similarly, requires investigation at arsenic exposure levels typical of U.S. exposures. We propose to investigate these relations by conducting nested case-control studies of squamous cell carcinoma of the skin (SCC) in two prospective cohort studies; the Nurses' Health Study (women) and the Health Professionals' Follow-up study (men), and by conducting a population-based case-control study in an area of Taiwan where exposure to arsenic through drinking water is still substantial. From the U.S. prospective studies we will include 460 histologically-confirmed cases of SCC, and 224 cases of bladder cancer who had previously given us a set of toenail clippings. Toenail arsenic levels have been shown to be a sensitive measure of arsenic intake in chronically exposed populations, and we have shown then to be highly reproducible over a six year period. For each case of SCC and bladder cancer, a control (two controls for each bladder cancer case) will be selected at random, matched by year of birth and month of nail return. Nail specimens will be analyzed by atomic absorption spectrophotometry for arsenic. A detailed questionnaire will be completed by cases and controls which assesses unusual environmental arsenic exposures, and cumulative lifetime sun exposure, a known risk factor for squamous cell carcinoma. Prospective data are already available on phenotypic risk factors for squamous cell carcinoma (e.g. hair color, tendency to burn). Analyses will initially assess the potential for confounding of arsenic, chromium, and selenium levels by classic risk factors (phenotype and sun exposure). In southwestern Taiwan we will conduct a population-based case-control study of SCC and bladder cancer, building on a strong collaboration we have developed with the National Cheng-kung University Medical Center. Based on results from our pilot study, we expect 480 cases of SCC and 160 cases of bladder cancer.